3rd French-Romanian Colloquium on Medicinal Chemistry ......ACTA CHEMICA IASI, 22_2, 177-235 (2014) DOI: 10.2478/achi-2014-0015 Abstracts for 3rd French-Romanian Colloquium on Medicinal

ACTA CHEMICA IASI, 22_2, 177-235 (2014) DOI: 10.2478/achi-2014-0015

Abstracts

for

3rd French-Romanian Colloquium on Medicinal Chemistry, Iasi, Romania

October, 30 - 31 2014

178 Abstracts

TABLE OF CONTENT

Alina Ghinet C1. From microtubule-interacting agents to dual molecules acting on proteins farnesyltransferase and tubulin ..................................................................................................................................................... 182

Adam Daïch, Prof C2. Tandem/Domino Processes Involving Simple Cationic Species which Target the Heterocyclic Diversity with Great Biological Potential............................................................................................... 183

Iuliana Botez, Laurence Danober C3. A Brief History of AMPA Receptors Potentiators ........................................................................... 184

Jolanta Rousseau, Stephane Menuel, Cyril Rousseau, Jelena Dodonova, Sigitas Tumkevičius and Eric Monflier

C4. Green access to heterocycles: aqueous media or solventless reactions? .......................................... 185 Abdallah Hamze

C5. 1,1-Diarylethylenes synthesis: A platform for discovery in chemistry and biology ........................ 186 Cristina M. Uritu, Andrei I. Dascalu, Dragos Peptanariu, Stelian S. Maier Bogdan C. Simionescu, Mariana Pinteala

C6. Non-viral vectors for gene therapy................................................................................................... 187 Leiv K. Sydnes

C7. Heterocycles of Medicinal Interest from Conjugated Alkynones .................................................... 188 Ion Grosu

C8. Macrocycles, porous polymers and self-assembled aggregates with potential applications in Medicinal Chemistry............................................................................................................................... 189

Sandrine Moreau-Pedragosa, François Lefoulon C9. White Biotechnology: A tool for Medicinal Chemistry and Pharmaceutical Development ............ 190

Pr Régis Millet C10.1. Conformationally Constrained Analogs of 4-Oxo-1,4-dihydroquinoline-3-carboxamide: Medicinal Chemistry Approach Leading to the Discovery of the First CB2 Cannabinoid Receptor Agonist Orally Active Against Experimental Colitis. ............................................................................ 191

Na tascha Leleu-Chavaina, Aurélien Tourteaua, Mathilde Body-Malapelb, Virginie Andrzejaka,Amélie Barczyka, Madjid Djouinab, Benoit Rigoc, Pierre Desreumauxb, Philippe Chavattea, Régis Milleta

C10.2. 3-Carboxamido-5-aryl-isoxazoles: new CB2 agonists and FAAH inhibitors for the treatment of colitis....................................................................................................................................................... 192

Dr Emmanuelle Lipka C11. Séparation chirale par chromatographie en phase supercritique .................................................... 193

Ionel I. Mangalagiu C12. Biological Activity of Some New Azaheterocycles....................................................................... 194

Marius Stefan, Mircea O. Apostu, Lucian G. Bahrin and Lucian M. Birsa O1. Tricyclic flavonoids with 1,3-dithiolium substructure: Synthesis and antibacterial activity ........... 195

Liliana Lucescu, Elena Bîcu, Dalila Belei, Benoît Rigo, Philippe Gautret, Alina Ghinet O2. A selective synthesis of quinolines versus enamines ....................................................................... 196

Benoît Rigo O3. Sels de N-acyliminium et induction de chiralité .............................................................................. 197

Alin C. Dîrțu, Camelia Bușilă, Aurel Nechita, Aurel Pui and Adrian Covaci O4. Persistent organic pollutants and their metabolites in human serum from obese children living in Eastern Romania ..................................................................................................................................... 198

Laura Ion1, Claudia Andries, Lucian Hritcu, Brian Gau, Michael Gross and Brînduşa Alina Petre O5. Mass spectrometric based approaches for studying aggregation of ß-amyloid peptide.................. 199

M.C. Al-Matarneh, R. Danac, I. Mangalagiu O6. Synthesis and antimycobacterial properties of new derivatives of 1,7-phenanthroline ................... 200

Iuliana Moise, Alina Ghinet, Sergiu Shova and Elena Bicu O7. Unexpected synthesis of new aza-indolizino-indolizines ................................................................ 201

3rd French-Romanian Colloquium on Medicinal Chemistry, Iasi, Romania 179

Daniela Ailincai, Luminita Marin, Mihai Mares, Bogdan C. Simionescu O8. The synthesis and characterization of new imino-chitosan biopolymeric films with antimicrobial properties ................................................................................................................................................ 202

Cristina-Maria Abuhaie O9. Conception, synthèse et évaluation de l’efficacité de nouveaux stimulateurs de défense des plantes (SDPs)..................................................................................................................................................... 203

Gina-Mirabela Dumitriu, Elena Bîcu, Dalila Belei, Benoît Rigo, Philippe Gautret, Alina Ghinet O10. Silylated assisted synthesis of aminals with potential microtubule-interacting properties ............ 204

Laura Ion, Claudia Andrieș, Ștefan Slamnoiu, Gabi Drochioiu, Michael Przybylski and Brîndușa Alina Petre

P1. Pathophysiological oxidative protein modifications: nitration versus hydroxylation of tyrosine .... 205 Gina-Mirabela Dumitriu, Elena Bîcu, Dalila Belei, Benoît Rigo, Philippe Gautret, Alina Ghinet

P2. Design, synthesis, and biological evaluation of novel pyrrolidinone-bridged analogues of Combretastatin-A4.................................................................................................................................. 206

Germain Homerin, Davy Baudelet, Philippe Gautret, Benoît Rigo, Xavier Dezitter, Emmanuelle Lipka3 and Alina Ghinet

P3. Synthesis and Anti-inflammatory Activity of Some P2X7 Antagonists ........................................... 207 Liliana Lucescu, Alina Ghinet, Joëlle Dubois, Sergiu Shova, Dalila Belei, Elena Bîcu

P4. Synthesis and biological evaluation of some new triazinyl-isoxazole derivatives ........................... 208 Ioana-Maria Simionca, Mariana Pinteala and Harm-Anton Klok

P5. Synthesis of cyclic PHEMA brushes via post-polymerization loop closure .................................... 209 Cristina-Maria Abuhaie, Elena Bicu, Dalila Belei, Philippe Gautret, Benoît Rigo, and Alina Ghinet1

P6. Synthesis and biological evaluation of new indolizine derivatives as antitumoral agents ............... 210 E. Landagaray, S. Yous, P. Berthelot, E. Lipka

P7. Conception, synthèse et évaluations pharmacologiques de ligands naphtofuraniques des récepteurs de la mélatonine. ..................................................................................................................................... 211

Andreea Cârâc, Rodica Mihaela Dinică, Geta Cârâc and Rica Boscencu P8. Spectral Study of New Ln - Heterocyclic Combinations ................................................................. 212

Ioana Otilia Ghinea, Simon Bonte, Rodica Mihaela Dinica, Bianca Furdui, Lidia Favier and Martine Demeunynck

P9. Antioxidant Potential of a New Family of Pyridinium Compounds................................................. 213 Daniela Dîrțu1, Roberta Cernat, Elena Hanganu, Adrian Covaci4 and Alin C. Dîrțu

P10. Organochlorine pesticides and polychlorinated biphenyls in human serum from Iasi, Romania, and their relation to non-Hodgkin lymphoma prevalence ............................................................................. 214

Gabriela Petrea-Ioneasa, Mihaela Petrea-Ioneasa, Ana Maria Rusu, Anca Gitman, Nela Bibire, Romeo Iulian Olariu, and Cecilia Arsene

P11. Reversed phase high performance liquid chromatographic assay method of active pharmaceutical ingredients in anti-tuberculosis 2-fixed dose combination tablets.......................................................... 215

Alina-Giorgiana Negru, Ghiorghita Zbancioc, Ionel Mangalagiu, Cecilia Arsene, and Romeo Iulian Olariu

P12. Physico-chemical behaviour of newly synthesized organic compounds. A reality between expectations and experimental evidences ............................................................................................... 216

Carmen Dumea, Elena Bîcu, Dalila Belei, Luminiţa Marin P13. Synthesis and self-assembling of phenothiazine and pyridine-N-oxide based AIE-active triazoles................................................................................................................................................................ 217

Carmen Dumea, Dalila Belei, Elena Bîcu P14. New triazole-indolizine derivatives with potential anticancer activity........................................... 218

Alexandra Rotaru, Elena Bîcu, Sergiu Şova, Dalila Belei P15. 1,3-Dipolar cycloaddition reaction of 1-carboxymethyl-pyridinium bromide with ethyl propiolate................................................................................................................................................................ 219

Maria Prodan, Simona Ştefanovici, Elena Bîcu, Dalila Belei P16. A facile synthesis of 2H-1,4-benzoxazin-2-ones............................................................................ 220

Simona Ştefanovici, Elena Bîcu, Dalila Belei P17. Synthesis and anticancer activity of new indolizine derivatives .................................................... 221

Laura G. Sarbu, Henning Hopf, and Lucian M. Birsa P18. Selenium halide induced bridge formation in [2.2]paracyclophanes.............................................. 222

180 Abstracts Eena Pahontu1, Diana-Carolina Ilies, Sergiu Shova, Codruta Paraschivescu, Mihaela Badea, Aurelian Gulea, Tudor Rosu

P19. Synthesis, Characterization, Crystal Structure of Copper(II) Complexes Containing an ON Donor Schiff Base. Antimicrobial Activity ...................................................................................................... 223

Steluta Gosav, Dan Maftei, Nicoleta Paduraru, Mihail Lucian Birsa P20. Vibrational spectroscopic studies on 3-(N,N-diethyldithiocarbamate)-2-(4-methoxyphenyl)chroman-4-one.............................................................................................................. 224

Steluta Gosav1 and Hélène Jamet P21. Molecular docking study of anticancer flavonoids......................................................................... 225

Stefania Racovita, Silvia Vasiliu, Maria-Andreea Lungan, Marcel Popa, Ion Bunia and Daniela Dirtu P22. Design of new drug delivery systems based on ion exchangers ..................................................... 226

Natalia Bairac P23. Synthesis and Anti-proliferative Activity of Coordinative Combination of Copper, Cobalt, Nickel and Zinc with 2-acetylpyridine Semi- and Thiosemicarbazone and their 4-Phenyl Substituents........... 227

Aurelian Gulea, Natalia Bairac,Victor Tsapkov, Poirier Donald P24. Di(-S)-bis{chlorin-[phenyl(pyridine-2-il)methanone-tiosemicarbazone (1-)]copper} as an Inhibitor of Breast Cancer T-47D Cells Proliferation............................................................................. 228

Olga Tagadiuc, Olga Stirba, Lilia Andronache, Olga Garbuz, Veaceslav Popa P25. Bioactive coordination compounds action on the intensity of the oxidative stress and antioxidant system activity in animals under physiological ...................................................................................... 229

Veronica Sardari, Olga Tagadiuc, Valeriana Pantea, Olga Știrba P26. Influence on new bioactive compounds on carbohydrate metabolism markers in experimental liver disease..................................................................................................................................................... 230

Maria Bîrcă, Aurelian1 Gulea, Victor Tapkov, Tatiana Codita, Alexandra Melnic P27. Activité Antibactérienne de Composés de Coordination de Cuivre et Nickel avec l’Isatine β-(N-pyridin-2-yl)thiosemicarbazone.............................................................................................................. 231

Aurelian Gulea, Anastasia Paholnitcaia, Victor Tsapkov, Larisa Sofroni P28. Synthesis, structure and in vitro antiproliferative activity of some hydrazones ............................. 232

Aurelian Gulea, Vasilii Graur, Elena Zariciuc, Anastasia Anachii, Victor Tsapkov and Valeriu Rudic P29. Antimicrobial Effect of 3d-Metal Coordination Compounds with 2,4-Pentanedione bis(4-Allylthiosemicarbazone) ......................................................................................................................... 233

Olga Stirba, Larisa Procopisin, Lilia Andronache, Olga Tagadiuc,Valentin Gudumac P30. Influence of bioactive coordination compounds on erythrocyte glutathione system in asthma ..... 234

Valentin Gugumac, Olga Garbuz, Vasilii Graur, Victor Tsapkov, Aurelian Gulea P31. In Vitro Antioxidants and Antilipoxygenase Activity Of Some Thiosemicarbazones and Their Non-Platinum Coordination Compounds ............................................................................................... 235


Comité d’organisation du 3ème Colloque Franco-Roumain de Chimie Médicinale :

(Organizing committee) Comité d’organisation du 3ème Colloque Franco-Roumain de Chimie Médicinale:

Prof. dr. Vasile Işan - Recteur de l’Université « Al. I. Cuza », Iasi, Roumanie Prof. dr. Elena Bîcu - Faculté de Chimie, Université « Al. I. Cuza », Iasi, Roumanie Dr. Alina Ghinet - École des Hautes Etudes d'Ingénieur, Lille, France Prof. dr. Benoît Rigo - École des Hautes Etudes d'Ingénieur, Lille, France Conf. dr. Philippe Gautret - École des Hautes Etudes d'Ingénieur, Lille, France Dr. Solo Goldstein - Institut de Recherches Servier, Croissy-sur-Seine, France Conf. dr. Lucian Bîrsă - Faculté de Chimie, Université « Al. I. Cuza », Iasi, Roumanie Lect. dr. Dalila Belei - Faculté de Chimie, Université « Al. I. Cuza », Iasi, Roumanie Lect. dr. Alin Dîrțu- Faculté de Chimie, Université « Al. I. Cuza », Iasi, Roumanie Asist. drd. Dan Maftei- Faculté de Chimie, Université « Al. I. Cuza », Iasi, Roumanie

(Scientific committee) Comité scientifique du 3ème Colloque Franco-Roumain de Chimie Médicinale:

Acad. Prof. dr. Marius Andruh - Académie Roumaine, Université Bucarest, RO Prof. dr. Elena Bîcu (Bâcu) - Université “Alexandru Ioan Cuza”, Iasi, RO Conf. dr. Lucian Bîrsă - Directeur Département Chimie, Université “Alexandru Ioan Cuza”, Iasi, RO Prof. dr. Adam Daïch – Editeur associé Med. J. Chem., Université du Havre, Le Havre, FR Dr. Joëlle Dubois - Directeur de recherche, Institut de Chimie des Substances Naturelles (CNRS),

Gif-sur-Yvette, FR Dr. Patrick Genissel - Directeur Pôles d'Expertise Recherche & Biopharmacie Vice-Président

Recherche & Développement, Institut de Recherches Servier, Suresnes, FR Dr. Alina Ghinet - Enseignant-Chercheur, École des Hautes Etudes d'Ingénieur, Lille, FR Dr. Solo Goldstein - Conseiller Scientifique Diversité Chimique, Institut de Recherches Servier,

Croissy-sur-Seine, FR Prof. dr. Jean-Pierre Hénichart - Professeur Emérite, Faculté de Médecine H. Warembourg, Lille, FR Prof. dr. Benoît Rigo - Responsable Pharmacochimie, École des Hautes Etudes d'Ingénieur, Lille, FR

182 Abstracts C1. From microtubule-interacting agents to dual molecules acting on proteins

farnesyltransferase and tubulin

Alina Ghinet*

UCLille, EA 4481 (GRIIOT), Laboratoire de Pharmacochimie, HEI, Groupe HEI-ISA-ISEN, 13 rue de Toul, F-59046 Lille, France

After cardiovascular diseases, cancer is the second cause of mortality in the world.

Thus, it is necessary to study this disease and discover new anticancer drugs. Among others, we

are principally interested in melanoma treatment.

We have just developed several new dual inhibitors, drug-hybrids FTis / MTis, active

molecules on farnesyltransferase (FTase) and on tubulin polymerization (Figure 1). Their

biological potential on both interest proteins (FTase and tubulin), on 60-cell line panel and on

hybrid endothelial cells has already been confirmed. It is now necessary to deepen the

knowledge of concerned chemical families and consequently, the project is focalized first on the

design, the synthesis, the biological evaluation of new drug-hybrids FTis / MTis, and then the

selection of the most interesting dual inhibitors in order to investigate their antitumor activity in

vivo, their antivascular potential, and their ADME-Tox properties.

X

A B

Structure of new mixtes inhibitors FTI / MTI currently developped

zinc-chelatinggroups

connector

hydrophobefragments

Figure 1.

Acknowledgements: This work was supported by a grant of the Romanian Ministry of Education, CNCS-UEFISCDI, project number PN-II-RU-PD-2012-3-0426. We gratefully acknowledge the National Cancer Institute (NCI) for biological evaluation of compounds on their 60-cell panel.

* Corresponding author, e-mail address: [email protected]


C2. Tandem/Domino Processes Involving Simple Cationic Species which Target the Heterocyclic Diversity with Great Biological Potential

Adam Daïch, Prof.

URCOM, INC3M FR-CNRS 3038, EA 3221, UFR des Sciences & Techniques de l’Université du Havre, 25 Rue Philippe Lebon, B.P 540, F-76058 Le Havre Cedex, France; [email protected]

One of our major research areas consists of the development of new synthetic approaches potentially useful in

organic and bio-organic chemistry. In this type of activity, the Hazard is omnipresent and the events, unexpected, often bring new perspectives.

The synthetic methodologies we develop in our group since many years now have for heart the formation of N-

acyliminiums cations, as stable species which generated generally in acid medium.* These cationic intermediates, derived from racemic or chiral imides by regioselective reduction, are trapped in an intermolecular or intramolecular manner by diverse types of nucleophiles including heteroatoms such as O, S, Se and N. This provide, after an ultimate functional arrangements, new structures based on new, simple, original and effective processes.†,‡

Our general approach consists on aiming the molecular skeletons of pharmaceutical interest sensibly selected for

their biological evaluations. In addition, the choice of the target molecules is closely linked to that of the collaborators or mutually depending on the case.

In this presentation, the illustration of these processes comes through few major applications which we shall

present. Also the main factors pivotal during these reactions as well as the synthetic and mechanistic aspects will be presented and discussed.

* Pour les revues récentes portant sur la �-cyclisation, voir : (a) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3817. (b) Maryanoff, B.

E.; Zhang, H. C.; Cohen, J. H.; Turchi, I. J.; Maryanoff, C. A. Chem. Rev. 2004, 104, 1431. † (a) π-Cyclisation: Daïch, A.; Marchalín, Š.; Pigeon, P.; Decroix, B. Tetrahedron Lett. 1998, 39, 9187; Chihab-Eddine, A.; Daïch, A.; Jilale, A.;

Decroix, B. Tetrahedron Lett. 2001, 42, 573; Pesquet, A.; Daïch, A.; Van Hijfte, L. J. Org. Chem. 2006, 71, 5303; Pin, F.; Comesse, S.; Garrigues, B.; Marchalín, Š.; Daïch, A. J. Org. Chem. 2007, 72, 1181; Pesquet, A.; Daïch, A.; Coste, S.; Van Hijfte, L. Synthesis 2008, 1389. (b) S-Cyclisation: Hucher, N.; Daïch, A.; Netchitaïlo, P.; Decroix, B. Tetrahedron Lett. 1999, 40, 3363; Hucher, N.; Decroix, B.; Daïch, A. J. Org. Chem. 2001, 66, 4695; Hucher, N.; Pesquet, A.; Netchitaïlo, P.; Daïch, A. Eur. J. Org. Chem. 2005, 2758; Pesquet, A.; Daïch, A.; Decroix, B.; Van Hijfte, L. Org. Biomol. Chem. 2005, 3, 3937. (c) Tandem ion thionium/S-Cyclisation: Hucher, N.; Daïch, A.; Decroix, B. Org. Lett. 2000, 2, 1201; Hamid, A.; Oulyadi, H.; Daïch, A. Tetrahedron 2006, 62 6398. (d) O-Cyclisation: Mamouni, A.; Daïch, A.; Marchalín, Š.; Decroix, B. Heterocycles 2001, 54, 275; Sikoraiova, J.; Marchalín, Š.; Daïch, A.; Decroix, B. Tetrahedron Lett. 2002, 43, 4747; Cul, A.; Chihab-Eddine, A.; Pesquet, A.; Marchalín, Š.; Daïch, A. J. Heterocycl. Chem. 2003, 40, 499. Pesquet, A.; Van Hijfte,L.; Daïch, A. Arkivoc 2010, viii, 27; Comesse, S.; A. Martel, A.; Daïch, A. Org. Lett., 2011, 13, 4004. (e) N-Cyclisation: Fogain-Ninkam, A.; Daïch, A.; Decroix, B.; Netchitaïlo, P. Eur. J. Org. Chem. 2003, 4273; Cul, A.; Daïch, A.; Decroix, B.; Sanz, G.; Van Hijfte, L. Tetrahedron 2004, 60, 11029; Oukli, N.; Comesse, S.; Chafi, N.; Oulyadi, H.; Daïch, A. Tetrahedron Lett. 2009, 50, 1459; Pin, F.; Comesse, S.; Daïch, A. Tetrahedron 2011, 67, 5564; Fleury, J.-F.; Netchitaïlo, P.; Daïch, A. Synlett 2011, 1821.

‡ Daïch, A.; Ghinet, A.; Rigo, B. Addition to N-Acyliminium Ions of Heteroatoms such as Oxygen, Nitrogen, Sulfur, and Selenium as Internal Nucleophiles. In: Gary A. Molander and Paul Knochel (eds.), Comprehensive Organic Synthesis, 2nd Edition, Vol. 2, Chap. 2.21; Oxford: Elsevier; 2014. pp. 682-742.

184 Abstracts

C3. A Brief History of AMPA Receptors Potentiators

Iuliana Botez1*, and Laurence Danober2

1Medicinal Chemistry, Institut de Recherches Servier, 125 Chemin de Ronde, 78290 Croissy-sur-Seine, France

2Neuropsychiatry Drug Discovery, Institut de Recherches Servier, 125 Chemin de Ronde, 78290 Croissy-sur-Seine, France

The amino acid L-glutamate is the major excitatory neurotransmitter in the brain and it

plays a major role in learning and memory processes. Two distinct families of L-glutamate

receptors have been described: the ionotropic - ligand-gated ion channels – iGluRs, and the

metabotropic - G-protein-coupled receptors - GPCRs. Following their sensitivity to selective

agonists, iGluRs have been sub-divided into three classes: AMPA, NMDA and kainate receptors.

Reports early ‘90s indicated that molecules reducing the desensitization of AMPA receptors

through a positive allosteric modulation may be useful agents in the treatment of CNS disorders

characterized by learning and memory impairments such as Alzheimer disease, Parkinson disease,

schizophrenia or depressive disorders. Compounds belonging to two distinct chemical classes have

been described: the benzamides early represented by aniracetam, and the benzothiadiazines early

represented by cyclothiazide and IDRA21. From these starting points lots of successors have been

developed by several pharmaceutical companies such as Cortex, Eli-Lilly, Organon, GSK, Pfizer,

Servier.

A huge amount of work was done at Servier around benzothiadiazine structures: compound

S 18986 entered the clinic late ‘90s but was finally discontinued. The next generations of

compounds provided several preclinical candidates. Among them, a large series of original pyrido-,

thieno- and benzothiadiazines has been developed in collaboration between the Servier Research

Institute in France and Liège University in Belgium. The present communication will be focused on

the medicinal chemistry around the benzothiadiazine derivatives – design, synthesis, in vitro and in

vivo evaluation, structure-activity relationships.

* Corresponding author, tel. +33 155 728 099, [email protected] (Iuliana Botez)


C4. Green access to heterocycles: aqueous media or solventless reactions?

Jolanta Rousseau1*, Stephane Menuel1, Cyril Rousseau1, Jelena Dodonova2, Sigitas Tumkevičius2 and Eric Monflier1

1 Université Lille Nord de France, CNRS UMR 8181, Unité de Catalyse et de Chimie du Solide UCCS, UArtois, Faculté des Sciences Jean Perrin, rue Jean Souvraz, SP18, 62307

Lens Cedex, France 2 Vilnius University, Department of Organic Chemistry, Naugarduko 24, 03225 Vilnius,

Lithuania

Today, green chemists and medicinal chemists closely cooperate to develop reactions not only chemo-, regio-, stereo-and enantio-controlled, but also economic and environmentally friendly. The development of novel, simple and cleaner synthetic protocols through the valorization of biomass, the use of catalytic process as well as alternative media ranks among the most important green chemistry principles. Among them, organic reactions in aqueous media and mechanochemistry have attracted much recent attention.

Water is one of the most abundant, cheapest, and environmentally friendly solvents. The discovery of new reagents and catalysts for the production of novel transformations or make a classic reaction more efficient is a very promising area of research. In the last two decades, native and modified cyclodextrins (CD) have been used as nano-reactors in various organic reactions as oxidation, addition, hydrolysis and even more recently in multicomponent cyclisation reactions in water. Furthermore, these supramolecules are inexpensive natural cyclic oligosaccharides. CD can be recovered and reused in subsequent reactions without loss of activity.

One of the main challenges in medicinal chemistry is the design and synthesis of biologically active molecule which calls for clean procedures avoiding the use of harmful organic solvent.

We will discuss herein, a new and efficient catalytic protocol to synthesize various heterocycles using (β-CD) as organocatalyst and also as mass transfer agents in aqueous biphasic conditions. In the second time we will report green alternative for access to heterocyclic compound in solvent less condition by means of mechanochemistry.

Acknowledgements The autors gratefully acknowledge two students Edita Vaiciunaite and Liudvikas

Akelis for their contribution on the subject. We are thankful to Campus France and PHC Gilibert for the partial support for one of the parts of this work.

References

S. Menuel, J. Rousseau, C. Rousseau, E. Vaiciunaite, J. Dodonova, S. Tumkevicius, E. Monflier. Eur. J. Org. Chem. 2014, 4356-4361; C. Rousseau, J. Rousseau, S. Menuel, E. Vaiciunaite, L. Akelis, J. Dodonova, S. Tumkevicius, E. Monflier Green Chem. 2014 (submitted).

* Corresponding author, tel. +33 321 791705, e-mail address [email protected]

186 Abstracts

C5. 1,1-Diarylethylenes synthesis: A platform for discovery in chemistry and biology

Abdallah Hamze*

Laboratoire de Chimie Thérapeutique, Equipe Labellisée Ligue Contre le Cancer, LabEx LERMIT, Faculté de Pharmacie, Université Paris-Sud, CNRS, BioCIS-UMR 8076, 5 rue J.-B.

Clément, Châtenay-Malabry, Paris, F-92296, France. http://www.biocis.u-psud.fr/?-HAMZE-Abdallah-Associate-professor-

Since 2007, we have particularly studied the reactivity of N-tosylhydrazones as

intermediates in reactions catalyzed by transition metals (Pd and Cu). These tosylhydrazones, generating in situ metal carbenes are likely large synthetic applications, as we have already shown (see scheme below).1 The advantage of these methods over conventional couplings lies in the fact that the organometallic compound is no longer used in stoichiometric amount. Under this method, various poly-substituted alkenes are prepared in a convergent way. A chemical library of olefinic compounds has been established and tested for their tubulin polymerization inhibition and cytotoxic activities. These results will be presented here.

* (a) Roche, M.; Hamze, A.; Brion, J.-D.; Alami, M. J. Org. Chem. 2013, 78, 445-454; (b) Roche, M.; Hamze, A.; Brion, J.-D.; Alami, M.

Org. Lett. 2013, 15, 148–151. (c) Aziz, J.; Brachet, E.; Hamze, A.; Peyrat, J.F; Bernadat, G.; Morvan, E.; Bignon, J.; Wdzieczak-Bakala, J.; Desravines, D.; Dubois, J.; Tueni, M.; Yassine, A.; Brion, J.D.; Alami, M. Org. Biomol. Chem. 2013, 11, 430-442.

* Abdallah HAMZE, tel. +33 146835498, e-mail address [email protected]


C6. Non-viral vectors for gene therapy

Cristina M. Uritu1, Andrei I. Dascalu1, Dragos Peptanariu1, Stelian S. Maier1,2, Bogdan C. Simionescu1,3, Mariana Pinteala1*

1Center of Advanced Research in Bionanoconjugates and Biopolymers, “Petru Poni” Institute of Macromolecular Chemistry of Romanian Academy, 41A Grigore Ghica Voda

Alley, 700487 Iaşi, România 2Department of Textile and Leather Chemical Engineering, „Gheorghe Asachi” Technical

University of Iasi, 67 Dimitrie Mangeron Blvd., 700050, Iaşi, România 3Department of Natural and Synthetic Polymers, Institution, „Gheorghe Asachi” Technical

University of Iasi, 67 Dimitrie Mangeron Blvd., 700050, Iaşi, România

Gene therapy is one of the most outstanding challenges in modern medicine, and consequently, in the last decade, extensive studies were performed mainly in the field of replacement of defective genes with fully functional copies. In this respect, the nucleic acids chains to be inserted into the cells are generally incorporated into engineered viral or non-viral vectorsi. Non-viral vectorization of DNA has certain advantages against viral methods, including the ability of large scale production and the simplicity of use, besides the decrease of the occurrence of undesirable immune response. This is why non-viral carriers are of actual interest, and are developed preferentiallyii.

Polyethylene imine (PEI) is one of the most investigated polycation as transfectant entity, due to its abundantly positive charged amine groups. PEI molecule itself, although very effective in DNA packaging and release, shows a high cytotoxicity when tested in cell cultures. Therefore it is aimed to conjugate PEI with various molecules in order to enhance the transfection efficiency in parallel with the cell viability. Biodegradability represents another severe issue, when the biological functionality of the cells must be preserved in vivo. The transfection efficiency of PEI is depending on its molecular weight: PEI with molecular weight less than 2 kDa has been proved to be non-toxic, while those in the range 5÷25 kDa are more suitable for gene transfer, although an increased cytotoxicity became inherent. A convenient strategy to increase transfection efficiency and to simultaneously decrease the cytotoxicity was found to be the coupling of low molecular weight PEIs (maximum 2 kDa) together, to form conjugates of 14÷30 kDa.iii In the context of the above mentioned theory, the present study demonstrate a pathway to synthesize dendrimer-like compounds containing hyperbranched low molecular weight PEI placed around different cores, such as fullerene C60 or β-cyclodextrin. To reduce the potential cytotoxicity of PEI and simultaneously to increase the biocompatibility of the transfectant carrier, PEG chains were also introduced. EYFP plasmid was used to evidentiate the gene transfer mediated by the synthesized carriers. Acknowledgements: This work was supported by the PNII-PCCE-ID-2011-2-0028 project. References:

i L. Novo, E. Mastrobattista, C. F. van Nostrum, W. E. Hennink. Targeted Decationized Polyplexes for Cell Specific Gene Delivery. Bioconjugate Chem. 2014, 25, 802−812. ii M. K. Yu, J. Park, S. Jon. Targeting Strategies for Multifunctional Nanoparticles in Cancer Imaging and Therapy. Theranostics 2012, 2, 3-44. iii M. L. Forrest, J. T. Koerber, D. W. Pack. A degradable polyethylenimine derivative with low toxicity for highly efficient gene delivery. Bioconjugate Chem. 2003, 14, 934-40.

188 Abstracts

C7. Heterocycles of Medicinal Interest from Conjugated Alkynones

Leiv K. Sydnes

Department of Chemistry, University of Bergen, Allégt. 41, 5007 Bergen, Norway

Ring opening of 1,1-dibromo-2-chloro-2-ethoxycyclopropane gives 3,3,4,4-tetraethoxy-1-butyne (TEB) (1) as the only product in very good yield [1,2]. This acetylene is very densely functionalized, and by taking advantage of the chemical properties of the various functional groups, a variety of compounds have been synthesized [4-7].

We are currently investigating the reactivity of derivatives of 1, e.g. 2 and 3 [Z = H, Bn, Bz,

RC(O), SiR3], towards a range of mononucleophiles and bisnucleophiles. These studies have resulted in a number of new products, and in the lecture the focus will be on syntheses of a variety of heterocyclic compounds which have been prepared in a regiospecific fashion and in very good yields.

References 1. Leiv K. Sydnes, Bjarte Holmelid, Ole H. Kvernenes, Marcel Sandberg, Mari

Hodne, and Einar Bakstad, Tetrahedron 2007, 63 (2007) 4144-4148. 2. Bjarte Holmelid, Ole H. Kvernenes, Mari Hodne and Leiv K. Sydnes, ARKIVOC 2008, (vi),

26-41. 3. Leiv K. Sydnes and Stig Valdersnes, Pure Appl. Chem. 2007, 79, 2137-2142. 4. Leiv K. Sydnes, Bjarte Holmelid, Stig Valdersnes, Myagmarsuren Sengee, and Kjartan

Boman, Jordanian J. Chem. 2007, 2, 105-116. 5. Leiv K. Sydnes, Bjarte Holmelid, Ole H. Kvernenes, Stig Valdersnes, Mari Hodne and

Kjartan Boman, ARKIVOC 2008, (xiv), 242-268. 6. Stig Valdersnes and Leiv K. Sydnes, Eur. J. Org. Chem. 2009, 5816-5831. 7. Leiv K. Sydnes, Bjarte Holmelid, Myagmarsuren Sengee, and Miriam

Hanstein, J. Org. Chem. 2009, 74, 3430-3443.


C8. Macrocycles, porous polymers and self-assembled aggregates with potential applications in Medicinal Chemistry

Ion Grosu

"Babeş-Bolyai" University, Faculty of Chemistry and Chemical Engineering, Department of Chemistry, Arany Janos 11, 400028, Cluj-Napoca

The synthesis of various macrocycles (I) and cryptands (II) exhibiting phenothiazine, thiophene, triazine or tris(1,3-dioxan-2-yl)benzene units was carried out using classic procedures for macrocyclization reactions (etherification, esterification, acetylenic coupling) but also by an original method based on the Suzuki-Miyaura cross-coupling reaction (Scheme 1).

The formation of supramolecular aggregates by hydrogene bonding (III, Scheme 1) starting from di- and tripodands exhibiting triazine, tris(1,3-dioxan-2-yl) or bicyclo[3.3.1]nonane central units and pendant arms decorated with H-donating and H-accepting groups were revealed by single crystal X-ray diffractometry, mass-spectrometry and NMR methods.

Porous polymers (IV, Scheme 1) showing a tridimensional structure based on tetraphenyladamantane or spirobifluorene units were obtained by acetylene coupling or Sonogashira cross-coupling reactions. These polymers revealed large specific surfaces (300-1000 m2/g) and high absorption properties.

. Scheme 1

References:

1. Medrut, I., Turdean, R., Gropeanu, R., Pop, F., Toupet, L., Hădade, N. D., Bogdan, E., Grosu, I. Tetrahedron Lett. 2013, 54, 1107. 2. Demeter, D., Lar, C., Roncali, J., Grosu, I. Tetrahedron Lett. 2013, 54,1460. 3. Pascanu, V., Circu, M., Socaci, C., Terec, A., Soran, A., Grosu, I. Tetrahedron Lett. 2013, 54, 6133 4. Circu, M., Soran, A., Hadade, N. D., Rednic, M., Terec, A., Grosu, I. J. Org. Chem. 2013, 78, 8722 5. Pop, F., Socaci, C., Terec, A., Condamine, E., Varga, R. A., Raț, C. I., Roncali, J. Grosu, I. Tetrahedron, 2012, 68, 8581. 6. Petran, A.; Terec, A.; Bogdan, E.; Soran, A.; Lakatos, E.; Grosu, I. Tetrahedron 2014, 70, 6803. 7. Circu, M., Pascanu, V., .., Terec, A., Socaci, C., Grosu, I. CrystEngComm 2012, 14, 632. 8. Golban, M. L., Pascanu, V., Hǎdade, N. D., Pop, L., Socaci, C., Grosu, I. Synthesis 2014, 1229.

190 Abstracts

C9. White Biotechnology: A tool for Medicinal Chemistry and Pharmaceutical Development

Sandrine Moreau-Pedragosa*, François Lefoulon

Synthesis Department, Research and Biopharmacy Centres, Technologie Servier, 45000 ORLEANS, FRANCE

The Pharmaceutical Development of a Drug Product is a long and extremely costly process. Unfortunately, this process is unlikely to get any easier, as more and more stringent regulations are imposed on the perilous road to obtaining Product Licences.

An answer to overcoming such difficulties may lie in the application of white biotechnology (biotransformations and biocatalysis). Difficult steps, or low-yielding reactions, may be simplified thus leading to major gains in overall selectivities and yields.

We herein present a range of examples whereby different reactions of special interest have been made possible through the application of biotransformations and biocatalysis.

In our group we use the “Microbial Model of Drug Metabolism” to access the synthesis of drug metabolites. Such metabolites are usually formed during the in vivo enzymatic transformations of their parents drugs and may often exhibit different toxicities or pharmacological activities. Their isolation and purification however remains time-consuming and therefore highly costly. Microbial biotransformation offers a convenient way of obtaining such metabolites in a clean and cost-effective manner. Such reactions may also allow the metabolite to be isolated in large quantities, thus facilitating their characterisation and use in further studies.

We shall therefore discuss some cases whereby the use of biotransformations has helped to generate new functionalised molecules as NCE or scaffolds for generating NCE allowing easy access to “chemical biodiversity”.

As well as being applied, white biotechnology may also be exploited to obtain API’s intermediates.

As active pharmaceutical ingredients (APIs) become increasingly more sophisticated, the Pharmaceutical Chemist needs to come up with ever-more effective synthetic strategies to produce these substances. Classical organic synthetic approaches, whether linear or convergent, often limit the availability of material for subsequent steps due to poor yields and/or over-complicated reactions. Here we will present a “case study” from a marketed drug.

* Corresponding author, tel +33 (0) 238 238 065, e-mail address [email protected]


C10.1. Conformationally Constrained Analogs of 4-Oxo-1,4-dihydroquinoline-3-carboxamide: Medicinal Chemistry Approach Leading to the Discovery of the First CB2 Cannabinoid Receptor Agonist Orally Active Against Experimental

Colitis.

Pr Régis Millet

Institut de Chimie Pharmaceutique Albert Lespagnol, Université de Lille 2, EA4481, 3 Rue du Professeur Laguesse, BP83, 59006 Lille

Inflammatory bowel disease (IBD) represents a group of chronic inflammatory lesions of unknown etiology that affect the digestive tract. The CB2 cannabinoid receptor emerged as a promising therapeutic target in the treatment of these pathologies. Indeed, this GPCR has been identified within the gastrointestinal tract and plays a key role in the regulation of intestinal inflammation. Additionally, the CB2 receptor agonists have been shown to exert an anti-inflammatory effect both in intestinal epithelial cells and in experimental models of colitis in mice. In vitro experiments highlighted that CB2 receptor activation results in suppression of the release of pro-inflammatory cytokines. Data from in vivo studies emphasized the importance of this receptor in mediating protection against experimental colitis.

Our groups previously described a series of 4-oxo-1,4-dihydroquinoline-3-carboxamide as selective ligands of the CB2 receptor. One of the commonly used strategies in drug design to increase affinity and selectivity of a given “flexible” lead for its pharmacological target is to conformationally constrain it to mimic the so-called bioactive conformation. Therefore, we designed constrained analogues of the 4-oxo-1,4-dihydroquinoline-3-carboxamide series based on a 2H-pyrazolo[4,3-c]quinolin-3(5H)-one scaffold.

The present study shows that 2H-pyrazolo[4,3-c]quinolin-3(5H)-ones are potent and selective CB2 agonists. The rigidification approach applied resulted in increased affinity for the CB2 receptor but also improved the selectivity over the CB1 receptor, while not altering the functional activity. ALICB459, the lead of this series, exerts a very strong protective effect in the experimental model of TNBS-induced colitis. This effect was achieved after oral administration and was shown to be dose-dependent.

192 Abstracts C10.2. 3-Carboxamido-5-aryl-isoxazoles: new CB2 agonists and FAAH

inhibitors for the treatment of colitis

Natascha Leleu-Chavain1, Aurélien Tourteau1, Mathilde Body-Malapel2, Virginie Andrzejak1,Amélie Barczyk1, Madjid Djouina2, Benoit Rigo3, Pierre Desreumaux2,

Philippe Chavatte1, Régis Millet1

The endocannabinoid system (ECS) includes two G-protein-coupled receptors (CB1 and

CB2), endogenous ligands, named endocannabinoids, and several biosynthesis and degradation enzymes as the fatty acid amide hydrolase (FAAH) or the monoacylglycerol lipase (MAGL)).1-3 The modulation of the ECS through the activation of cannabinoid receptors and the inhibition of degradation enzymes consists in a promising therapeutic strategy. Indeed, this system has shown beneficial effects in several diseases like osteoporosis,4 pain5 or chronic inflammation disorders.6

More specifically, the ECS is implicated in gut homeostasis, gastrointestinal motility and Inflammatory Bowel Diseases (IBD).7-8 These diseases, which two main forms are Crohn’s disease and ulcerative colitis, affect more than 2.2 million people in Europe and are characterized by an inflammation of the gastrointestinal tract due to a hyperactivity of the immune system. Recently, it has been demonstrated that cannabinoid receptors are overexpressed in vivo and in patients suffering from IBD.7-9 The beneficial role of CB2 in intestinal inflammation has been highlighted in several in vivo and in vitro studies.10-13 Moreover, the genetic invalidation of FAAH in animals with 2,4-dinitrobenzene sulfonic acid (DNBS)-induced colitis significantly reduced tissue inflammation.14 It has also been showed that URB597, a FAAH inhibitor, increased survival and decreased inflammation in mice suffering from trinitrobenzene sulfonic acid (TNBS)-induced colitis.15-16

According to the implication of the endocannabinoid system in IBD, we decided in our laboratory to develop selective CB2 agonists and FAAH inhibitors to treat these diseases. 3-carboxamido-5-aryl-isoxazoles designed as CB2 agonists were evaluated for their FAAH inhibition activity.17 The pharmacological results led to identify structure–activity relationships enabling to switch cannabinoid response from CB2 agonists to FAAH inhibitors. Two compounds were selected for their FAAH and/or CB2 activity, and evaluated in a colitis model for their anti-inflammatory activity. Results showed that these compounds inhibit the development of DSS-induced acute colitis in mice and then, are interesting leads to explore new drug candidates for IBD.

1. De Petrocellis, L.; Cascio, M. G.; Di Marzo, V. Br. J. Pharmacol. 2004, 141, 765. 2. Howlett, A. C.; Barth, F.; Bonner, T. I.; Cabral, G.; Casellas, P.; Devane, W. A.; Felder, C. C.; Herkenham, M.; Mackie, K.; Martin, B. R.; Mechoulam, R.; Pertwee, R. G. Pharmacol. Rev. 2002, 54, 161. 3. Lambert, D. M.; Fowler, C. J. J. Med. Chem. 2005, 48, 5059. 4. Rossi, F.; Siniscalco, D.; Luongo, L.; De Petrocellis, L.; Bellini, G.; Petrosino, S.; Torella, M.; Santoro, C.; Nobili, B.; Perrotta, S.; Di Marzo, V.; Maione, S. Bone 2009, 44, 476. 5. Ibrahim, M. M.; Deng, H.; Zvonok, A.; Cockayne, D. A.; Kwan, J.; Mata, H. P.; Vanderah, T. W.; Lai, J.; Porreca, F.; Makriyannis, A.; Malan, T. P., Jr. Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 10529. 6. Berdyshev, E. V. Chem. Phys. Lipids 2000, 108, 169. 7. Alhouayek, M.; Muccioli, G. G. Trends Mol. Med. 2012, 18, 615. 8. Izzo, A. A.; Sharkey, K. A. Pharmacol. Ther. 2010, 126, 21. 9. Stintzing, S.; Wissniowski, T. T.; Lohwasser, C.; Alinger, B.; Neureiter, D. Histol. Histopathol. 2011, 26, 735. 10. Qamri, Z.; Preet, A.; Nasser, M. W.; Bass, C. E.; Leone, G.; Barsky, S. H.; Ganju, R. K. Mol. Cancer Ther. 2009, 8, 3117. 11. Ihenetu, K.; Molleman, A.; Parsons, M. E.; Whelan, C. J. Eur. J. Pharmacol. 2003, 458, 207. 12. Alhouayek, M.; Lambert, D. M.; Delzenne, N. M.; Cani, P. D.; Muccioli, G. G. FASEB J. 2011, 25, 2711. 13. Storr, M. A.; Keenan, C. M.; Zhang, H.; Patel, K. D.; Makriyannis, A.; Sharkey, K. A. Inflamm. Bowel Dis. 2009, 15, 1678. 14. Massa, F.; Marsicano, G.; Hermann, H.; Cannich, A.; Monory, K.; Cravatt, B. F.; Ferri, G. L.; Sibaev, A.; Storr, M.; Lutz, B. J. Clin. Invest. 2004, 113, 1202. 15. Storr, M. A.; Keenan, C. M.; Emmerdinger, D.; Zhang, H.; Yüce, B.; Sibaev, A.; Massa, F.; Buckley, N. E.; Lutz, B.; Göke, B.; Brand, S.; Patel, K. D.; Sharkey, K. A. J. Mol. Med. 2008, 86, 925. 16. D’Argenio, G.; Valenti, M.; Scaglione, G.; Cosenza, V.; Sorrentini, I.; Di Marzo, V. FASEB J. 2006, 20, 568. 17. Tourteau, A.; Leleu-Chavain, N.; Body-Malapel, M.; Andrzejak, V.; Barczyk, A.; Djouina, M.; Rigo, B.; Desreumaux, P.; Chavatte, P.; Millet, R. Bioorg. Med. Chem. Lett. 2014, 24, 1322.


C11. Séparation chirale par chromatographie en phase supercritique

Dr Emmanuelle Lipka

Univ Lille Nord de France, UFR de Pharmacie, EA 4481, Laboratoire de Chimie Analytique, Lille F-59000, France

Un grand nombre de molécules pharmaceutiques comportent un ou plusieurs centres

d’asymétrie donnant naissance à des énantiomères aux propriétés pharmacologiques différentes. Depuis le drame socio-sanitaire de la Thalidomide®, une attention particulière a été portée sur la chiralité. Aujourd’hui chaque isomère doit faire l’objet d’une étude pharmaco-toxicologique complète au cours de son cycle de développement. La synthèse asymétrique est le premier moyen d’obtention de ces énantiomères. Cependant elle présente plusieurs inconvénients : elle ne génère qu’un seul isomère à la fois, le risque de racémisation est important et cette voie est longue, fastidieuse et couteuse. Les techniques chromatographiques préparatives se sont alors développées comme alternative à la synthèse. La plus connue est la Chromatographie Liquide Haute Performance (CLHP), mais depuis quelques années elle tend à être détrônée par la Chromatographie en Phase Supercritique (CPS) qui met en œuvre, comme phase mobile, un fluide porté au-delà du point critique par un contrôle adéquat de la température et de la pression, le plus souvent du dioxyde de carbone (CO2). La CPS possède des caractéristiques propres, liées aux propriétés des fluides supercritiques, à savoir une masse volumique comparable à celle d'un liquide, associée à une plus faible viscosité et une grande compatibilité avec les détecteurs de la Chromatographie en Phase Gazeuse (CPG) et de la CLHP, qui en font une technique très performante :

des sélectivités importantes sont observées en raison des interactions entre les solutés, la phase stationnaire et la phase mobile que l'on peut faire varier par l'ajout de faibles quantités (< 30%) de modificateurs organiques, polaires (méthanol, acétonitrile) ou apolaire (heptane) à la phase supercritique ;

la CPS, du fait qu'elle utilise majoritairement du CO2, atoxique, comme phase mobile à la place des solvants organiques généralement utilisés en CLHP, est une technique «verte». En effet, le CO2 peut être recyclé et purifié pour les applications à l'échelle préparative, grosses consommatrices de solvants ;

la CPS préparative présente, par ailleurs, l'avantage de permettre une récupération des solutés par simple détente de la phase mobile, les seules traces de solvants résiduels provenant des additifs polaires éventuellement ajoutés.

Une approche préparative [1] puis une approche analytique de cette nouvelle technologie,

plus écologique et plus rapide, à l’interface entre la CPG et la CLHP feront l’objet de cette présentation. Elle concernera l’étude de deux candidats médicaments ayant respectivement pour cible : un récepteur purinergique nouvellement identifié d’intérêt pharmacologique dans le traitement des Maladies Inflammatoires Chroniques de l’Intestin, et un récepteur couplé à une protéine G potentiellement impliqué dans le traitement du diabète. [1] Baudelet D, Schifano-Faux N, Ghinet A, Dezitter X, Barbotin F, Gautret P, Rigo B, Chavatte P, Millet R, Furman C, Vaccher C, Lipka E, Enantioseparation of pyroglutamide derivatives on polysaccharide based chiral stationary phases by high-performance liquid chromatography and supercritical fluid chromatography: A comparative study. J Chromatogr A. 2014 Oct 10;1363:257-269. e-mail author : [email protected]

194 Abstracts

C12. Biological Activity of Some New Azaheterocycles

Ionel I. Mangalagiu

“Al. I. Cuza” University of Iasi, Faculty of Chemistry, Bd. Carol 11, 700506 Iasi, Romania. Tel: +40+232 201343; fax: +40+232 201313; e-mail: [email protected]

Azaheterocycles are invaluable compounds demonstrating fascinating potential applications for medicine, opto-electronics, agriculture, etc.

As part of our ongoing research in the field of biologically active compounds with azahetrocycle skeleton, we report here the design, synthesis, structure and biological activity of some new fused and non -fused five and six member ring azaheterocycles. The syntheses were straight and efficient and were performed under microwave (MW) and ultrasound (US) irradiation as well as under conventional thermal heating (TH). A rational drug design was performed and show us that some certain fused and non -fused five and six member ring azaheterocycles are potential antimicrobials (antibacterial, antifungal and antimycobacterial), anticancer and grow up plant regulators.

Concerning the antibacterial and antifungal of our azaheterocycles, the obtained results show us that some compounds have a remarkable activity against Gram positive germs, very good activity against some Gram negative germs and fungus, comparative with standard drugs; in some cases the results were spectacular. The primary cycle high throughput screening reveals that several compounds are potent inhibitors against Mycobacterium tuberculosis, their antitubercular activity being superior to the second-line antitubercular drug Pyrimethamine and equal to Cycloserine. The MIC, MBC, LORA, intracellular (macrophage) drug screening, and MTT cell proliferation, indicate the intracellular drug effectiveness against Mtb of these compounds, the lack of toxicity, a significant activity against both replicating and non-replicating Mtb and, a bactericidal mechanism of action.

The anticancer activity against of some fused and non -fused five and six member ring azaheterocycles was tested against HeLa cell lines and against an NCI 60 human tumour cell line panel. Comparative with standard drugs, some of the tested compounds proved to have an excellent antitumor activity against HeLa cell lines and against Non-Small Cell Lung Cancer NCI-H460, Leukemia MOLT-4, Leukemia CCRF-CEM and Breast Cancer MCF7. Feasible explanations for anticancer efficiency of our azaheterocycles derivatives have been furnished, being correlated with the mechanisms of action. SAR correlations have been done.

The effect of some fused and non -fused five and six member ring azaheterocycles on germination and seedling growth was investigated. The tested compounds exhibited a general stimulating activity on the hypocotyls growth, especially at lower concentrations. A possible relationship between structure and biological activity are mentioned.

Acknowledgements. Authors are thankful to CNCS Bucharest, Romania, project PN-

II-DE-PCE-2011-3-0038, no. 268/05.10.2011, for financial support.


O1. Tricyclic flavonoids with 1,3-dithiolium substructure: Synthesis and antibacterial activity

Marius Stefan1, Mircea O. Apostu2, Lucian G. Bahrin2 and Lucian M. Birsa2*

1 Department of Biology, Al.I. Cuza University of Iasi, 11 Carol I, 700506 Iasi, Romania 2 Department of Chemistry, Al.I. Cuza University of Iasi, 11 Carol I, 700506 Iasi, Romania

The synthesis of new 3-dithiocarbamic flavonoids has been accomplished by the reaction of the corresponding 2-hydroxyaryl dithiocarbamates with aminals. These flavonoids were obtained as a mixture of diastereoisomers, the anti isomer being the major one. The heterocyclization of these compounds provided a little known class of tricyclic flavonoids bearing a 1,3-dithiolium-2-yl ring fused at the 3,4-carbon positions of the benzopyran moiety.

Sulfur containing flavanones and tricyclic flavonoids were tested for antibacterial activity against Staphylococcus aureus ATCC 25923 (Gram-positive) and Escherichia coli ATCC 25922 (Gram-negative), using disc diffusion assay with gentamicin as reference and minimum inhibitory concentrations were determined where activity was found present.

O

R1

R2

O

S

S N

R3

O

R1

R2

R3

S

S

N

X

While the tested flavanones did not yield the desired results, good antibacterial activities

were recorded for the tricyclic flavonoids. The introduction of the 1,3-dithiolium cation produced results comparable to those of gentamicin and in some cases, MIC values were less than 1g/ml.

The ion-dissociation vs. formation of a tight ionpair appears to be of significant importance on how cationic tricyclic flavonoids interact with bacteria. The major component of bacterial cell wall is represented by negatively charged phosphatidylethanolamine (70%). Thus, the positively charged 1,3-dithiolium flavonoids target the oppositely charged biological structures such as cell walls of microorganisms which leads to the leakage of intracellular substances.

* Corresponding author, tel. +40 232 201349, e-mail address [email protected] (Lucian Mihail Birsa)

196 Abstracts

O2. A selective synthesis of quinolines versus enamines

Liliana Lucescu1*, Elena Bîcu1, Dalila Belei1, Benoît Rigo2, Philippe Gautret2, Alina Ghinet1,2

1`Al. I. Cuza` University of Iasi, Faculty of Chemistry, Bd. Carol I nr.11, 700506 Iasi, Romania

2 UCLille, EA 4481 (GRIIOT), Pharmaceutical chemistry Laboratory, HEI, 13 rue de Toul, F-59046 Lille, France

Cytotoxicity of 1,3,5-triazine derivatives is well known as, for example, hexamethylmelamine (HMM) (1) that was discovered as an effective agent against breast, lung and ovarian cancer,1 but caused severe nausea and vomiting, and some structural analogues of 1 were prepared and tested.2 Over time, numerous structural modulations of the HMM consisting in the substitution of dimethylamino groups with another moieties such as dialkylamino, aryloxy, alkyloxy-, alkylaryl- or cyclic amines, have been reported.3 From these studies it was shown that nonsymmetrical substitution of s-triazine cycle and the replacement of the dimethylamino groups with methoxy units, maintained the antitumor potential. This was observed for compounds 2-5.2

N

N

N

MeO OMe

N

N

N

MeO OMe

OH

N

N

N

MeO OMe

CN

N

N

N

MeO OMe

HO

IG50(colon cancer ) = 0.4 µM IG50(ovarian cancer ) = 1.86 µM IG50(melanoma) = 2.09 µM IG50(lung cancer) = 4.9 µM

N

N

N

N

N N

Hexamethylmelamine1 2 3 4 5

Figure 1. Antitumoral s-triazine derivatives

During the synthesis of 2-ethynyl-4,6-dimethoxy-1,3,5-triazine 6, 2-((E)-2-chlorovinyl)-4,6-dimethoxy-1,3,5-triazine 7 was also isolated, as by-product issued from the addition of hydrochloric acid on the triple bond. This encouraged us to study the reactivity of compound 6 in the presence of primary and secondary amines. The reaction of 6 with a secondary amine has led us to the expected enamine 8, but after the reaction with primary aromatic amine, bearing three methoxy groups, unexpected quinoline 9 has been isolated.

N

N

N

MeO

MeO

N N

NMeO

OMe

N

6

8

N

N

N

OMe

OMe

7

ClN

MeO

OMe

MeO

N

NN

OMe

OMe

9

HCl

DCM / r.t. DCM / r.t.DCM / r.t.

Et2NHH2N

OMe

OMe

OMe

Scheme 1. Reactivity of 2-ethynyl-4,6-dimethoxy-1,3,5-triazine

Acknowledgment: This work was supported by the strategic grant POSDRU/159/1.5/S/137750, Project “Doctoral and Postdoctoral programs support for increased competitiveness in Exact Sciences research” cofinanced by the European Social Found within the Sectorial Operational Program Human Resources Development 2007 – 2013.

References:

1. Kumar, R.; Gupta, L.; Pal, P.; Khan, S.; Singh, N.; Katiyar, S. B.; Meena, S.; Sarkar, J.; Sinha, S.; Kanaujiya, J. K.; Lochab, S.; Trivedi, A. K.; Chauhan, P. M. S. Eur. J. Med. Chem. 2010, 45, 2265–2276.

2. Menicagli, R.; Samaritani, S.; Signore, G.; Vaglini, F.; Via, L. D. J. Med. Chem. 2004, 47, 4649–4652. 3. Coley, H. M. Gen. Pharm. 1997, 28, 177–182.

*Corresponding author, tel. +40 746 495623, e-mail address: [email protected] (Liliana Lucescu)


O3. Sels de N-acyliminium et induction de chiralité

Benoît Rigo*


Les sels de N-acyliminium sont des cations plans. L’addition de nucléophiles sur ceux-ci

conduit à des produits racémiques. Cependant, ils sont très sensibles aux contraintes stériques, et

lorsqu’un centre d’asymétrie est présent, l’induction d’un nouveau centre chiral est possible.

N

N O

H

H

H

O

OMe

NO CO2SiMe3

SiMe3

+

O

NO CO2SiMe3

OSiMe3

NO CO2SiMe3+

N

O

RO2CNO CO2R

HN

O

CO2HNO CO2H

H

N

O

NO OMeOMe

N

O

NOOMe+

N

O

NOOH+

R = SiMe3R = H

identique à

H+

électrochimie

HCl/H2O

B

A

La synthèse stéréosélective du composé B à partir de l’acide pyroglutamique disilylé A

illustre cet aspect de la chimie des sels de N-acyliminium.


198 Abstracts O4. Persistent organic pollutants and their metabolites in human serum from

obese children living in Eastern Romania

Alin C. Dîrțu1,2*, Camelia Bușilă3,4, Aurel Nechita3,4, Aurel Pui2 and Adrian Covaci1

1Toxicological Centre, Dept. of Pharmaceutical Sciences, University of Antwerp, Belgium 2Dept. of Chemistry, “Al. I. Cuza” University of Iasi, Romania

3Children Emergency Clinical Hospital ”Sf. Ioan” Galati, Romania 4Faculty of Medicine and Pharmacy,”Dunarea de Jos” University of Galati, Romania Organohalogenated contaminants (OHCs), such as polychlorinated biphenyls (PCBs),

organochlorine pesticides (OCPs), as well as brominated flame retardants (BFRs) were shown to be ubiquitous in the environment and humans. Contrarily to Western Europe where well-developed programs exist for the OHCs monitoring in humans, only limited information concerning the human exposure to such contaminants is available from Eastern European countries, such as Romania.1 In the present study, we have evaluated the levels and profiles of several PCB congeners and their hydroxylated metabolites, polybrominated diphenyl ethers, and selected OCPs in obese versus normal weight children living in Galați, Eastern Romania.

Serum samples were collected from obese children visiting the Children Emergency Clinical Hospital ”Sf. Ioan” Galati, Romania. These patients participate in a hospital monitoring program due to the diabetes mellitus pathology associated with obesity. Serum was sampled when children entered the monitoring program (N=47) while a control group (N=43) was randomly selected in a similar time interval (homogenously distributed for age and gender). Consistent with previous literature2, due to body dilution, higher levels were measured for the control group when compared to obese children although the results were adjusted for the serum total lipids. Among the measured contaminants, from the PCBs, the most important in term of levels were CB 180, 153, 138, 187 and 170 congeners with a contribution up to 75% to the total PCB levels. DDTs were the most abundant contaminants from the OCPs, with DDE being measured at the highest levels. Our results corroborate the hypothesis that some endocrine disrupting chemicals might play a role in the occurrence of obesity. In case of weight loss programs will follow later for the obese children, given the lipophilic nature of such contaminants, the increasing internal exposure dose might interfere with the children development.

The results included in this study show the high exposure of Romanian population to these

OHCs and therefore an extensive program for monitoring the contamination with OCPs, PCBs and BFRs in different Romanian environmental compartments becomes necessary in the light of adverse health effects reported for these contaminants.

Acknowledgements: This work was supported by the strategic grant

POSDRU/159/1.5/S/133652, co-financed by the European Social Fund within the Sectorial Operational Program Human Resources Development 2007 – 2013.

References 1. Dirtu AC, Jaspers VLB, Cernat R, Neels H, Covaci A. Environ. Sci. Technol. 44 (8),

2876-2883, 2010. 2. Dirtu AC, Dirinck E, Malarvannan G, Neels H, Van Gaal L, Jorens PG, Covaci A.

Environ. Sci. Technol. 47 (21), 12441-12449, 2013.

* Corresponding author, tel. +40 232 201308, e-mail address [email protected] (Alin C. Dirtu)


O5. Mass spectrometric based approaches for studying aggregation of ß-amyloid peptide

Laura Ion1, Claudia Andries1, Lucian Hritcu2, Brian Gau3, Michael Gross3 and Brînduşa Alina Petre1, 3*

1Departament of Chemistry, Al. I. Cuza University of Iasi, Romania 2 Department of Biology, Al. I. Cuza University of Iasi, Romania

3 Department of Chemistry, Washington University, St. Louis, Missouri, USA

Aging is a major risk factor for the neurodegenerative disorders such as Alzheimer’s disease (AD) and the number of AD patients is increasing worldwide. The accumulation of fibrillar plaques of ß-amyloid peptide (Aß) in the brain have been recognized as characteristics of AD [1]. Although circular dichroism, atomic force microscopy, electron microscopy, light scattering were directed at understanding these molecules, the biological mechanism of protein aggregation remains to be achieved. Understanding how this peptide assembles will provide new targets for developing aggregation modifiers that could potentially limit their toxicity. In our work, we are investigating the aggregating Aß (1-40) peptide as model systems by using mass spectrometric based approaches.

Various protein footprinting strategies were employed to study oligomerization of different neurodegenerative peptides/proteins: high resolution MS in combination with affinity-biosensor system, H/D amide exchange, and FPOP (fast photochemical oxidation of proteins). FPOP [2] is a chemical footprinting method whereby exposed amino-acid residues are covalently labeled by oxidation with hydroxyl radicals produced by the photolysis of hydrogen peroxide. Modified residues can be detected by standard trypsin proteolysis followed by LC/MS/MS, providing information about solvent accessibility of various residues of the protein.

Here, we present the FPOP data of ß-amyloid (1-40) peptide during different aggregation times. Experimentally, to obtain the oligomeric conformation, Aβ(1-40) peptide was used right after dissolution in HFIP followed by dilution with PBS at a concentration of 20µM. From time to time the aggregating solution was exposed to hydroxyl radicals produced in FPOP experiment, followed by quenching, trypsin digestion and mass spectrometric measurements. Using Mathcad, a mathematic algorithm program, FPOP data gave us indications of every single amino acid modification within different times of Aβ aggregation process. We observed that several C-terminal amino acids were not exposed to the oxidation after 4 to 7 days of ß-amyloid (1-40) peptide incubation. Also we observed several ß-amyloid (1-40) amino acids having a high dynamic during the aggregation process.

Acknowledgements The financial support by the Romanian National Authority for

Scientific Research, CNCS – UEFISCDI, project number PN-II-RU-TE-2011-3-0038 is gratefully acknowledged.

References

1. Minati L., Am. J. Alzheimers Dis. Demen. 2009, 24, 95-121. 2. Gau B. C., Sharp J. S., Rempel D. L., Gross M. L. Anal Chem. 2009, 81, 6563–6566.

* Corresponding author, tel. +40 232 201279, e-mail address [email protected]

200 Abstracts

O6. Synthesis and antimycobacterial properties of new derivatives of 1,7-phenanthroline

M.C. Al-Matarneh*, R. Danac1, I. Mangalagiu1

1Faculty of Chemistry, “Alexandru Ioan Cuza” University of Iasi, Romania;

Human tuberculosis (TB), a contagious disease caused by Mycobacterium tuberculosis (Mtb), remains the leading infectious disease among humans, claiming approximately 1.8 million life’s every year worldwide1. The association with HIV infection, and the emergence of multi-drug-resistant (MDR) and extensively drug-resistant (XDR) to Mtb, is a deadly synergistic factor for TB2-4.

Phenanthrolines polycyclic skeletons are present in sterols, sex hormones, cardiac glycosides, bile acids and morphine alkaloids. While 1,10-phenathroline derivatives have been widely studied both for synthesis and applications, much less interest has been shown for the other phenanthrolines because of difficulties in their synthesis.

As part of our ongoing research aiming the synthesis of novel anti-TB compounds with azaheterocycles skeleton5-6, we report here the design, synthesis, structure and in vitro antimycobacterial activity of new 1,7-phenanthroline derivatives.

Therefore, we synthesized new pyrrolo[1,2-i][1,7] phenanthroline derivatives via 3+2 cycloaddition reactions of the symmetrical and unsymmetrical dipolarophiles to the in situ generated cycloimmonium ylides from monoquaternary 1,7-phenanthrolinium salts. These salts were obtained by the reaction of 1,7-phenanthroline with halogenated ω-bromoacetophenone, α-bromoacetate or α-bromoamides. As dipolarophiles we used activated alkyne or alkene, achieving indolizines, tetrahydroindolizine or dihydroindolizine derivatives with polycyclic skeleton.

A selection of the new compounds was tested in order to determine their

antimycobacterial activity against Mycobacterium tuberculosis (Mtb), and a study of antitumoral properties of part of the new compounds is underway. References:

1 World Health Organization Tuberculosis Programme Available from: Global tuberculosis report/WHO/HTM/TB/2012.6. 2 Migliori, G. B., Lange, C., Centis, R., Sotgiu, G., Muetterlein, R., Hoffmann, H., Kliiman, K., De laco, G., Lauria, F.N., Richardson, M. D., Spanevello, A., Cirillo, D. M., Grp, T.S. Eur. Respir. J., 31, 1155 (2008).

3 Raviglione, M. C., Smith, I. M., N. Engl. J. Med, 356, 656 ( 2007). 4 Burman, W. J., Jones, B. E., Am. J. Respir. Crit. Care Med., 164, 7 (2001).

5 Danac, R., Daniloaia, T., Antoci, V., Mangalagiu, I. I., Lett. Drug Des. Discov., in press, DOI: 10.2174/1570180811666140819223501.

6 Danac, R., Mangalagiu, I., Eur. J. Med. Chem., 74, 664 ( 2013). This work was supported by the strategic grant POSDRU/159/1.5/S/137750, Project “Doctoral and Postdoctoral programs support for increased competitiveness in Exact Sciences research” cofinanced by the European Social Found within the Sectorial Operational Program Human Resources Development 2007 – 2013.

* * Corresponding author, tel. +40 0748683402, e-mail address [email protected]


O7. Unexpected synthesis of new aza-indolizino-indolizines

Iuliana Moise1, Alina Ghinet1,2, Sergiu Shova3 and Elena Bicu1,*

1Department of Chemistry, ”Alexandru Ioan Cuza” University of Iasi, Bulevardul Carol I nr. 11 Iasi, Romania

2Department of Chemistry, Textiles and Innovative Processes, École des Hautes Études d’Ingénieur, 13 Rue de Toul, 59046 Lille Cedex, France

3Institute of Macromolecular Chemistry ‘‘Petru Poni’’, 41A Grigore Ghica Voda Alley, 700487 Iasi, Romania

Due to the extent of cancer nowadays, the necessity to find a cure is constantly increasing. Two of the promising agents that inhibit cell growth are combretastatin A-4 and its analog, phenstatin, two molecules that target tubulin polymerization.1,2 In order to increase the anticancer potency of these compounds, various chemical modulations have been made. Some of the structural modifications that have been shown to maintain good activity against cell proliferation involve the usage of phenothiazine derivatives.3 Encouraged by these facts we have decided to synthesize new phenstatin and combretastatin analogs bearing the phenothiazine heterocycle. We also chose to use the indolizine moiety based on its various biological properties.4 Therefore, the general structure of the desired compounds is presented in Figure 1.

N

R

COOEt

OAr/Het

N

R

R'

O

N

S

R''

Figure 1.General structures of the target compounds

N

R

R'

O

N

S

The synthesis pathway for some indolizine derivatives provided an unexpected product. After investigating the molecule, we discovered a structure that possessed both an indolizine and a 1-aza-indolizine ring (Figure 2). All synthesized compounds have been characterized (IR, 1H and 13C NMR). They were submitted for biological screening at NCI and they will be tested for their ability to inhibit tubulin polymerization.

Figure 2. Structure of unexpected compound

References

1. Pettit, G. R.; Singh, S. B.; Boyd, M. R.; Hamel, E.; Pettit, R. K.; Schmidt, J. M.; Holgan, F. J. Med. Chem. 1995, 38, 1666-1672. 2. Pettit, G. R.; Grealish, M. P. et al. J. Med. Chem. 2000, 43, 2731-2737. 3. Abuhaie, C-M., Bicu, E., Rigo, B., Gautret, P., Belei, D., Farce, A., Dubois, J., Ghinet, Bioorg. Med. Chem. Lett. 2013, 23, 147-152. 4. Singh, G. S.; Mmatli, E. E. Eur. J. Med. Chem., 2011, 46, 5237-5257.

* Corresponding author, tel. +40 232 201307, e-mail address [email protected] (Elena Bîcu)

202 Abstracts O8. The synthesis and characterization of new imino-chitosan biopolymeric

films with antimicrobial properties

Daniela Ailincai1*, Luminita Marin1, Mihai Mares2, Bogdan C. Simionescu 1,3 1 ”Petru Poni” Institute of Macromolecular Chemistry of Romanian Academy – 41A, Aleea Gr. Ghica

Voda, Iasi, Romania 2

”Ion Ionescu de la Brad” University, Laboratory of Antimicrobial Chemotherapy, 8, Aleea Sadoveanu, Iasi, Romania

3 ”Gheorghe Asachi” Technical University of Iasi – 73, Strada Prof. Dimitrie Mangeron, Iasi, Romania

The pathogen colonization on medical implants, medical indwelling devices or simply medical devices which come into contact with patients represents one of the most important problems from both the financial and medical point of view, the infections caused by microorganisms being the main postsurgical complication. To overcome this problem, the development of new and really efficient materials with antimicrobial properties received considerable attention over the last years. The use of chitosan, a natural biopolymer, for the development of such materials, brings many other advantages, among all, very important being its lack of toxicity and its biocompatibility.

The objective of this study was to obtain imino-chitosan biopolymer films with antimicrobial properties in order to apply them as thin layer protective systems for medical devices. The imino-chitosan films have been obtained by condensation of the chitosan amino groups with different aldehydes, in aqueous medium, followed by slowly water evaporation. FTIR spectra of the obtained films showed significant changes compared to the chitosan, indicating the obtaining of the imine bond but also modifications regarding the supramolecular structure.

Wide angle X-ray diffraction measurements confirmed the self-assembling of the imino-chitosan biopolymer chains based on hydrophobic-hydrophilic layering. Contact angle and surface free energy determination indicated a higher biocompatibility of the new biopolymers as compared to chitosan, while the microbiological screening demonstrated their self-defense properties against three common and virulent pathogen agents encountered in care-associated diseases. It was concluded that the reversibility of imine bond promotes the self-assembling of the imino-chitosan biopolymer films into a lamellar morphology and, on the other hand, the slow release of the antimicrobial aldehyde in the microbiological culture.

Acknowledgements

This work was supported by a grant of the Romanian National Authority for Scientific Research, CNCS – UEFISCDI, project number PN-II-ID-PCCE-2011-2-0028.

* Corresponding author , tel: 0740474295, e-mail address: [email protected]


O9. Conception, synthèse et évaluation de l’efficacité de nouveaux stimulateurs de défense des plantes (SDPs)

Cristina-Maria Abuhaie*


Les stimulateurs de défense des plantes (SDPs) sont des biomolécules agissant comme un

« vaccin » sur la plante contre les bio-agresseurs, sans effet biocide direct. Les plantes possèdent en effet des mécanismes de défense naturels et intrinsèques qui sont activés en cas d’attaque par un bio-agresseur. Les SDPs sont des substances qui vont simuler ces signaux d’attaque, permettant ainsi à la plante de déclencher ses mécanismes de défense et donc de mieux résister en cas d’attaque réelle.1,2

La septoriose (Septoria tritici) est l’un des principaux bio-agresseurs du blé, pouvant détruire jusqu'à 40 % de celui-ci. La septoriose se reconnaît grâce aux taches présentes sur le feuillage. Elles peuvent être blanches et allongées ou brunes, de formes ovales ou rectangulaires. Au sein de ces taches, des pycnides noires (petits points noirs très visibles) sont présentes et caractéristiques de la maladie. Différentes méthodes de lutte peuvent être mises en œuvre pour limiter les contaminations par Septoria tritici.3 Une alternative pour lutter contre cette maladie est basée sur l'utilisation de fongicides conventionnels, mais leur utilisation est de plus en plus controversée. Ainsi, il existe un besoin grandissant de méthodes de lutte alternative. Les stimulateurs de défense des plantes (SDPs) peuvent être une solution respectueuse de l’environnement et de la santé humaine.

Dans le cadre d’une nouvelle thématique de recherche dans le laboratoire à l’interface chimie-biologie, nous nous sommes investis dans la synthèse des composés qui présentent une activité SDP sur le pathosystème blé-septoriose. La recherche de nouveaux bioproduits efficaces vis-à-vis de la septoriose du blé en s’appuyant sur la chimie de l’acide pyroglutamique, matière première renouvelable, a été appliquée dans le cadre de ce projet.

NH

OO

OH

NOO

OH

O

O

OAcide pyroglutamique stimulateur potentiel de défense des plantes

Cinq composés ont été obtenus à partir d’acides carboxyliques via la chimie des dérivés silylés. Ces composés sont actuellement en évaluation biologique in planta (en serre).

Remerciements : Ce projet de recherche est soutenu par le Groupe HEI-ISA-ISEN, Lille.

1. Shetty, N.P., Kristensen, B.K., Newman, M.-A., Møller, K., Gregersen, P.L., Jørgensen, H.J.L., Physiological and Molecular Plant Pathology, 62, 333–346, (2003).

2. O’Driscoll, A., Kildea, S., Doohan, F., Spink, S., Mullins, E., Trends in Plant Science, 19, 602-610, (2014). 3. Arraiano, L.S., Balaamb, N., Fenwickc, P.M., Chapmanc, C., Feuerhelmd, D., Howelle, P., Smith,S.J.,

Widdowsong, J.P., Browna, J.K.M., Plant Pathology, 58, 910–922, (2009).


204 Abstracts O10. Silylated assisted synthesis of aminals with potential microtubule-

interacting properties

Gina-Mirabela Dumitriu1, Elena Bîcu1, Dalila Belei1, Benoît Rigo2,3, Philippe Gautret2,3, Alina Ghinet1,2,3*

1Department of Organic Chemistry, Faculty of Chemistry, ‘Al. I. Cuza’ University of Iasi, B-dul Carol I, Nr. 11, Corp A, 700506 Iasi, Romania

2Univ Lille Nord de France, F-59000 Lille, France 3UCLille, EA GRIIOT (4481), Laboratoire de pharmacochimie, HEI, 13 rue de Toul, F-59046 Lille,

France

Alkylation of amines via oxidative Csp3–H bond activations has been reported by many groups. However, most of the reagents were limited to amides, sulfonamides, azoles, or anilines with strong electron withdrawing-groups.1–5 To the best of our knowledge, alkylation of anilines with Csp3–H bonds adjacent to a nitrogen atom via oxidative C–H bond activation is rarely realized, although it has been achieved in tandem cyclization reactions.6,7

Recently, a new method for synthesizing acyclic aminals by the iron-catalyzed or copper-catalyzed Csp3–H amination of lactams with arylamines under mild conditions was reported. However, in this papers the reactions with the anilines or the corresponding amines with electron-donating groups were not stable in this oxidizing reaction system.8,9

NH

O O

X

RN

R

O O

R1HN

R2

NH

NH

R2

O

R1HNR2

XR

N NH

R

R2O

Target compounds Scheme 1. General synthesis of the target compounds

NO O

R3

H2NR2

NNH

O

NHO

R2

R3

R3

Scheme 2. Synthesis of new quinoline derivatives

Acknowledgment: This work was supported by the strategic grant POSDRU/159/1.5/S/137750, Project “Doctoral and Postdoctoral programs support for increased competitiveness in Exact Sciences research” cofinanced by the European Social Found within the Sectorial Operational Program Human Resources Development 2007 – 2013 (PhD scholarship G.-M. D.).

References: 1. Zhang, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Org. Lett. 2007, 9, 3813–3816. 2. Harvey, M. E.; Musaev, D. G.; Du Bois, J. J. Am. Chem. Soc. 2011, 133, 17207–17216. 3. Xia, Q.; Chen, W.; Qiu, H. J. Org. Chem. 2011, 76, 7577–7582. 4. Zhang, J.; Hong Chan, P. W.; Che, C.-M. Tetrahedron Lett. 2005, 46, 5403–5408. 5. Xia, Q.; Chen, W. J. Org. Chem. 2012, 77, 9366–9373.

6. Zhang, C.; De, C. K.; Mal, R.; Seidel, D. J. Am. Chem. Soc. 2008, 130, 416–417. 7. Zeng, L.-Y.; Yi, W.-B.; Cai, C. Eur. J. Org. Chem. 2012, 2012, 559–566. 8. Sun, M.; Zhang, T.; Bao, W. Tetrahedron Lett. 2014, 55, 893–896. 9. Priyadarshini, S.; Amal Joseph, P. J.; Lakshmi Kantam, M. Tetrahedron 2014, 70, 6068–6074.

* Alina Ghinet, tel. +33/3 28 38 48 58, e-mail address [email protected]

In the present paper, we

describe the results for optimization of silylated assisted synthesis of N,N-aminals. General synthesis of the target compounds is represented in Scheme 1.

Unpredictably, some of these reactions conducted us to the synthesis of quinoline derivatives (Scheme 2).


P1. Pathophysiological oxidative protein modifications: nitration versus hydroxylation of tyrosine

Laura Ion1, Claudia Andrieș1, Ștefan Slamnoiu2, Gabi Drochioiu1, Michael Przybylski2 and Brîndușa Alina Petre1*

1Department of Chemistry, "Al. I. Cuza University", Iasi, Romania 2Department of Chemistry, Konstanz University, 78457, Konstanz, Germany

Nitration of tyrosine residues represents an oxidative post-translation modification in proteins. This occurs in physiological conditions and increases in several pathophysiological processes such as diabetes, chronic hepatitis, atherosclerosis, neurodegenerative disease, asthma and lung disease. Different in vivo pathways for tyrosine nitration are known in the literature, but peroxynitrite and heme peroxidase mediated modification are the most studied mechanisms.

In a previous proteomics study of sputum sample from patients with Cystic Fibrosis, the presumed nitrated proteins sites were investigated. While western blot analysis showed very low extend of protein nitration based on using anti-3-nitrotyrosine antibodies, the mass spectrometric data reveals novel oxidative protein modification, hydroxy-tyrosine containing peptide as endogenous modification [1].

In this study we have investigated the cross-reactivity of anti 3-nitro-tyrosine (NT) antibodies to nitrated/ hydoxylated tyrosine containing peptides. The peptides were synthesized by solid-phase peptide synthesis (SPPS), purified by reversed phase- high performance liquid chromatography (RP-HPLC), and characterized by electrospray (ESI) and matrix-assisted laser desorption-ionization (MALDI) mass spectrometry [2]. Binding affinities and specificities of synthetic peptides with different Tyr-modified sites were determined by using anti-nitrotyrosine antibodies in two immuno-analytical methods [3]. Dot blot analysis and surface acoustic wave biosensor (SAW biosensor) has been successfully applied for studying binding affinities and specificities of nitrated model peptides to a monoclonal anti-3NT-antibody. SAW technology in comparison with other immuno-analytical techniques was found to be a high performing tool for direct and rapid determinations of association/dissociation constants using only small amount of samples.

Acknowledgements This work was supported by the strategic grant POSDRU/159/1.5/S/137750 and the

Romanian National Authority for Scientific Research, CNCS–UEFISCDI, project number PN-II-RU-TE-2011-3-0038.

References

1. Petre B.A., Ulrich M., Stumbaum M., Bernevic B., Moise A., Döring G., Przybylski M. (2012), J. Am. Soc. Mass Spectrom, 23(11): 1831-1840. 2. Petre A., Youhnovski N., Lukkari J., Weber R., Przybylski M. (2005) Eur. J. Mass Spectrom. 11, 513-518. 3. Dragusanu M., Petre B.A., Slamnoiu S., Vlad C., Tu T., Przybylski M.(2010) J. Am. Soc. Mass Spectrom. 21, 1643-1648.

* Corresponding author: Brîndușa Alina Petre, tel. +40 232 201279, [email protected]

206 Abstracts

P2. Design, synthesis, and biological evaluation of novel pyrrolidinone-bridged analogues of Combretastatin-A4

Gina-Mirabela Dumitriu1, Elena Bîcu1, Dalila Belei1, Benoît Rigo2,3, Philippe Gautret2,3, Alina Ghinet1,2,3*

1Department of Organic Chemistry, Faculty of Chemistry, ‘Al. I. Cuza’ University of Iasi, B-dul Carol I, Nr. 11, Corp A, 700506 Iasi, Romania

2Univ Lille Nord de France, F-59000 Lille, France 3UCLille, EA GRIIOT (4481), Laboratoire de pharmacochimie, HEI, 13 rue de Toul, F-59046 Lille, France

Microtubule polymerization dynamics can greatly affect the ability of cells to change and maintain their

shape and undergo critical processes such as cell signaling and mitosis.1 Combretastatin-A4 (CA-4, I, Fig. 1) is one of the representative molecule of vascular disrupting agents that have been designed, synthesized, and tested in various biological models as potential therapeutic candidates for cancer treatment.2,3 Research on combretastatin A-4 in order to improve its in vivo activity led to the discovery of phenstatin (II, Fig. 1).4

Modifications of the ethylenic bridge from CA-4 or carbonyl group from phenstatin have also led to diverse structural variations that maintain cytotoxic properties. Five-membered heterocycles have been shown to be appropriate isosters for the ethylenic bridge. Consequently, examples that include furanone (III),5 isoxazole (IV),6 imidazole (V),7 triazole (VI),8 thiazolone (VII), (Fig. 1)9 have been reported in the literature.

Modifications made on the two phenyl rings led to hundreds of active compounds that possess desirable cytotoxicity while retaining varying degrees of antitubulin activities.10

Documents

3rd French-Romanian Colloquium on Medicinal Chemistry ......ACTA CHEMICA IASI, 22_2, 177-235 (2014) DOI: 10.2478/achi-2014-0015 Abstracts for 3rd French-Romanian Colloquium on Medicinal